Synthetic Developmental Tissue Engineering of Human Hair Follicles

项目摘要 人类皮肤替代物(HSE)已为因以下原因而导致皮肤严重脱落的患者提供了一种有效的治疗方法 烧伤、溃疡和遗传性皮肤病；然而，它们仍然有各种限制，包括生存能力差和 缺少附属物或毛发密度不匹配。我们最近通过以下方法提高了皮肤移植的存活率 建立HSE中微血管构型的方法。另一方面，它仍然是一种盛行的 由于长期培养的人毛乳头，设计带有毛囊的功能性皮肤移植面临的挑战 体外培养的细胞(DPC)失去了诱导毛发的能力。这个项目的总体目标是设计出可行的和 使用培养的人类细胞的功能皮肤等价物和附属物。我们将采用生物工程， 遗传学和系统生物学方法将培养的DPC和真皮成纤维细胞重新编程为毛发 诱导性细胞。然后，这些单元将用于生成带有头发的3D蒙皮等效物，从而启用 开发真正有功能的皮肤替代品，用于严重皮肤/头发脱落的患者。特别是，我们将 使用i)微制造技术来概括3D毛囊微环境(微环境 方法)和ii)反向工程基因网络分析以重新编程毛发诱导基因签名 培养的DPC和成纤维细胞(遗传学方法)。最后，利用我们最近成立的 血管化技术，我们将开发可存活的HSE，在植入后，可以可控地再生 由于加强了血管重建，头发和头发保持完全整合。再生整根头发的能力 来自培养的人类细胞的卵泡将对医学治疗产生压倒性的积极影响 不同类型的脱发、大疱性表皮松解症以及慢性伤口、严重感染和烧伤，都是 其中主要的未得到满足的医疗需求。产生毛发皮肤的能力是至关重要的一步。 朝着制造真正有功能的人类皮肤迈进，这将标志着再生技术在概念上的巨大进步 治疗皮肤和毛囊疾病的医学方法，如脱发，以及改善 严重皮肤损伤导致毁容疤痕的后果。

Project Summary Human skin equivalents (HSEs) have provided an effective therapy for patients with significant skin loss due to burns, ulcers and genetic skin diseases; however they still have various limitations including poor viability and lack of appendages or mismatch in hair density. We have recently improved the viability of skin grafts by establishing a method to micropattern vasculature in HSEs. On the other hand, it still remains a prevailing challenge to engineer functional skin grafts with hair follicles since long-term cultured human dermal papilla cells (DPCs) in vitro lose their hair-inducing capacity. The overall goal of this project is to engineer viable and functional skin equivalents with appendages using cultured human cells. We will employ bioengineering, genetics and systems biology approaches to reprogram cultured DPCs and dermal fibroblasts into hair inductive cells. These cells will then be used to generate hair-bearing 3D skin equivalents, enabling the development of truly functional skin substitutes for patients with significant skin/hair loss. In particular, we will use i) microfabrication techniques to recapitulate 3D hair follicle microenvironment (microenvironmental approach) and ii) reverse engineering gene network analysis to reprogram hair inductive gene signatures of cultured DPCs and fibroblasts (genetic approach). Finally, taking advantage of our recently established technique for vascularization, we will develop viable HSEs that, after engraftment, can controllably regenerate hair and remain fully integrated due to enhanced revascularization. The ability to regenerate an entire hair follicle from cultured human cells will have an overwhelming positive impact on the medical management of different types of alopecia, epidermolysis bullosa as well as chronic wounds, severe infections, and burns, all of which represent major unmet medical needs. The ability to generate a hair-bearing skin is a crucial step towards making a truly functional human skin and would mark a dramatic conceptual advance in regenerative medicine approaches to disorders of the skin and hair follicle, such as hair loss, as well as improve the outcome of severe skin injuries leading to disfiguring scars.